Osteoporosis is a major public health threat in the U.S. today affecting at least 44 million Americans and up to 55% of people over 50 years of age. It is estimated that 30-50% of women and 15-30% of men will suffer a fracture related to osteoporosis in their lifetime, in other words, 1 in 3 women and 1 in 5 men will experience an osteoporotic fracture. By the year 2050, the worldwide incidence of hip fracture is projected to increase by ~300%. The combined lifetime risk for hip, forearm, and vertebral fractures coming to clinical attention is ~40%, which is equal to the risk for cardiovascular disease. Calcitonin isa polypeptide hormone with 32 amino acids and has a molecular mass of about 3500. This hormone is involved in the complex regulation of blood calcium level by inhibiting bone resorption. Calcitonin is used therapeutically for the treatment of osteoporosis, Paget's disease, and hypocalcaemia of different origin. Currently, multiple injections of calcitonin is a common practice in treating the above conditions due to its short biological half-life. It has been demonstrated that daily administration of salmon calcitonin (sCT) effectively reduces bone turnover and maintains bone mass in men and postmenopausal women. The maximum effect is reached after 2 months of continuous administration of sCT. The long-term goal of this project is to develop a polymer solution based controlled delivery system of sCT, which can deliver the hormone at a predefined rate for two months after a single subcutaneous injection. This strategy would avoid daily injections and provide optimum benefits to the osteoporotic patients. We propose to study two specific aims: (1). To synthesize and characterize temperature sensitive poly (ethylene glycol) - poly (lactide-co-glycolide) - poly (ethylene glycol) (PEG-PLGA-PEG) triblock copolymers with increasing PLGA chain length. In situ gel forming copolymer solution based controlled delivery systems of the sCT will be prepared and studied for rheological characteristics and in vitro release profiles of sCT. The stability of the released sCT as well as sCT in the gel will be evaluated using Fourier transform infrared spectroscopy, circular dichroism, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, native sodium dodecyl sulfate-polyacrylamide gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and high performance liquid chromatography techniques. Further, in vitro biocompatibility of the delivery systems will be evaluated by MTT assay. (2). To study in vivo absorption, bioassay, and therapeutic efficacy of sCT delivery systems in the glucocorticoid induced osteoporosis rat model. In vivo biocompatibility of the delivery systems will be studied in rats by light microscopic studies of the excised tissue from the injection site. The proposed efforts will significantly contribute to the development of temperature sensitive polymer based delivery systems in the form of injectable solution to deliver sCT at a controlled rate for a longe duration (~ 2 months) after a single subcutaneous injection. Development of such a novel therapeutic system is critical for successful treatment of bone diseases, especially osteoporosis in men and postmenopausal women, in order to improve patient quality of life.